Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells

Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the US and no significant treatment is currently available. Here, we describe the effect of crocetinic acid, which we purified from commercial saffron compound crocetin using high performance liquid chromatography. Crocetinic acid inhibits proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. In addition, it induced apoptosis. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, crocetinic acid decreased the number and size of the pancospheres in a dose-dependent manner, and suppressed the expression of the marker protein DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1) suggesting that crocetinic acid targets cancer stem cells (CSC). To understand the mechanism of CSC inhibition, the signaling pathways affected by purified crocetinic acid were dissected. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Crocetinic acid inhibited the expression of both Shh and smoothened. Finally, these data were confirmed in vivo where the compound at a dose of 0.5 mg/Kg bw suppressed growth of tumor xenografts. Collectively, these data suggest that purified crocetinic acid inhibits pancreatic CSC, thereby inhibiting pancreatic tumorigenesis.

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

“…Gupta et al also showed significantly lower tumor volume among PCs with an initially high population of CD133+ cells (10-25% of cells) in mice treated with lovastatin in combination with paclitaxel when compared to a control group, which suggests that lovastatin may sensitize these cells to paclitaxel [173]. In the Rangarajan et al study it was found that crocetinic acid suppressed the growth of the tumor and the expression of CD133 and DCLK1 [174]. Another interesting result observed during a study with the kinase inhibitor XMD8-92, showed that injecting this drug caused a reduction in xenograft volume and weight, as well as significant downregulation of DCLK1 expression [175].…”

Epigallocatechin‐3‐gallate enhances differentiation of acute promyelocytic leukemia cells via inhibition of PML‐RARα and HDAC1

“…The cells were treated with EGCG (12.5–100 μM) or ATRA (10 μM), and then incubated with PI reagent. The quantification of apoptosis and necrosis was carried out using FACS Calibur (BD Biosciences) flow cytometer followed by analysis with Flowjo software (TreeStar Inc., USA; Rangarajan et al, ).…”

The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer

“…In cancer cells and tumors, cholesterol biosynthesis is generally deregulated and increased through an upregulation/activation of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and sterol regulatory element-binding protein, an increase in its import via the low-density lipoprotein receptor and scavenger receptor class B type I, an inhibition of its export by the ABC transporters, ABCA1, ABCG1, a greater amount of storage of cholesteryl esters and the activation of different receptors and signaling pathways such as PI3K/Akt/mTor, TP53, or Hedgehog (3,(8)(9)(10)(11). Interestingly, while cholesterol and side-chain oxysterols activate Smoothened in Hedgehog signaling (12,13), endogenous B-ring oxysterols inhibit this pathway (14).…”